New therapeutic approaches are desperately needed in Alzheimer's disease research. Therefore, our research program over the past year has focused on the use of pharmacologic agents in innovation therapeutic and drug challenge strategies. We have continued to study the cognitive and behavioral effects of the anticholinergic agent, scopolamine and have attempted to better understand its antimemory effects. By combining scopolamine with the tripeptide, thyrotropin releasing hormone (TRH), or the stimulant, amphetamine, we are dissecting the various components of this pharmacologic challenge strategy. We have discovered that a significant part of scopolamine's amnestic effect can be reversed with these drugs, thus demonstrating that other non-cholinergic processes are involved in memory and cognition. These findings are being pursued in a new generation of challenge studies which win help identify those other processes. From a complementary perspective, the Unit is also developing new stra- tegies in therapeutic drug trials of Alzheimer's Disease patients. Building on our previous work which showed that the monoamine oxidase inhibitor, 1-deprenyl, was helpful in the symptomatic treatment of this disorder, we are now going on to investigate potentially neuroprotective effects of 1-deprenyl in Alzheimer patients during long-term trials. We are also attempting to expand the horizon of dementia therapies by combining dif- ferent pharmacologic agents in a single therapeutic trial. Our ongoing study of combination therapies (eg. physostigmine with 1-deprenyl) is the first such attempt at pharmacologic synergy in Alzheimer's Disease and, if successful may well represent a new therapeutic strategy for the 1990's.